We generated mice with disruption of Gs-alpha expression from the maternal allele in the central nervous system (mBGsKO) by mating females heterozygous for a Gs-alpha floxed allele with loxP recombination sites surrounding Gs-alpha exon 1 to males with a nestin promoter-cre recombinase transgene. Mice with similar loss of Gs-alpha expression in the central nervous system on the paternal allele (pBGsKO) were generated with reciprocal crosses. pBGsKO mice had normal survival and overall phenotype with no effect on glucose or energy metabolism or serum lipids as determined by multiple experimental approaches (body weight and composition, organ weights, serum chemistries and hormones, glucose and insulin tolerance tests, metabolic rate and food intake measurements). In contrast, mBGsKO developed severe obesity with diabetes, severe insulin resistance, and hypertriglyceridemia. The obesity began to develop after 5 weeks. Studies in younger mice indicate that the insulin resistance and glucose intolerance began to develop prior to obesity, indicating an effect on glucose metabolism independent of obesity. Further studies in mBGsKO mice showed that the obesity was primarily the result of reduced sympathetic nervous system activity and energy expenditure and reduced expression of brown adipose tissue genes associated with energy dissipation, such as uncoupling protein 1 (UCP1), with no primary effect on food intake. We hypothesized that mBGsKO mice may be defective the ability of the melanocortin system to stimulate sympathetic nervous system activity and energy expenditure. To test this hypothesis, acute food intake and energy expenditure responses to a melanocortin agonist (MTII) were measured. There were no differences between pBGsKO mice and controls, and there was little effect on the ability of MTII to inhibit food intake in mBGsKO mice. However, the ability of MTII to stimulate energy expenditure was markedly reduced in mBGsKO mice as compared to controls. Moreover mBrGsKO mice have impaired diet-induced thermogenesis and reduced heart rate and blood pressure. Overall these results confirm that Gs-alpha pathways in the central nervous system are critical regulators of metabolism and that maternal Gs-alpha mutations in mice (and most likely Albright hereditary osteodystrophy patients) results from Gs-alpha imprinting in one or more site in the central nervous system. In situ hybridization studies showed that Gs-alpha is imprinted in the paraventricular nucleus of the hypothalamus (PVN), a known site of melanocortin action and metabolic regulation. We more recently examined mice with loss of Gs-alpha in the ventral medial hypothalamus (VMH) using Sf1-cre and see no major effects on regular diet, but some resistance to diet-induced obesity. Mice with PVN-specific Gs-alpha deficiency using Sim1-cre (also loss of Gs-alpha in a couple of other sites) show moderate effects on energy balance and glucose metabolism, more prominent in males, but not to the extent as mBrGsKO mice. This suggests that other regions in addition to the PVN are involved in the parent-of-origin effects on glucose metabolism, which we will examining in the near future. We have also begun experiments on mice with loss of Gs-alpha in glucose-excitable POMC (proopiomelanocortin) neurons. Results to date show them to be hyperglycemic with reduced insulin levels, suggesting a defect in central glucose sensing leading to a insulin secretory defect from pancreatic beta cells. These mice are also hypocortisolemic, presumably due to the fact that the ACTH (adrenocorticotropin) neurons (which are also POMC neurons) lack Gs-alpha and therefore cannot respond to CRH (corticotropin releasing hormone).